Type 2 diabetes mellitus (T2D) results from insulin resistance, increased hepatic glucose production, and impaired islet function which is likely a key determinant of whether T2D develops. However, the molecular mechanisms responsible for islet dysfunction are incompletely defined and largely unknown. To address these challenges, we submit this application in response to FOA-DK-18-016, Human Pancreas Analysis Program for Type-2 Diabetes (HPAP-T2D). Our collaborative and interdisciplinary team will interrogate T2D human pancreatic tissue and islets from clinically phenotyped or ?staged? donors using the range of experimental approaches outlined in the RFA and new experimental techniques. Our team will: (1) Collect and process the pancreas and islets from individuals with; (a) prediabetes, (b) T2D diabetes treated with only diet and/or oral medications, (c) T2D diabetes treated with insulin, and (d) from normal controls, and determine their genetic risk for T2D; (2) Use the broad range of molecular techniques requested by the RFA and integration with new and emerging experimental approaches to comprehensively phenotype the pancreatic islets isolated from designated donor groups to understand molecular changes in T2D; (3) Use state-of-the-art approaches coupled with new cutting-edge multiplexing technology, to comprehensively analyze pancreatic tissue architecture in cellular and extracellular compartments from designated donor groups; (4) Integrate data from these studies into the comprehensive, open-access, searchable PANC-DB database, and help develop this resource to serve the community of scientists interested in understanding human pancreatic and islet biology in T2D; (5) Create, enhance, and leverage partnerships with complementary programs like HPAP-T1D, HIRN, IIDP, nPOD, AMP-T2D, and QUOD. Our group of investigators has been collaborating extensively on studies of the human pancreas and islets, including T2D pancreatic organs with associated clinical information as called for in this RFA. We are committed to harmonization, integration, and co- registration of data from the different approaches with the ultimate output of our efforts being a comprehensive T2D profile available to all investigators interested in T2D through PANC-DB. Thus, the successful formation of our proposed program should lead to improved understanding of the T2D pathogenesis as well as the design of therapies capable of preventing and/or reversing the disorder.